CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

Eman M Zaghloul, Olof Gissberg, Pedro M D Moreno, Lee Siggens, Mattias Hällbrink, Anna S Jørgensen, Karl Ekwall, Rula Zain, Jesper Wengel, Karin E Lundin, C I Edvard Smith

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Abstract

Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion of the CAG trinucleotide repeat region in exon 1 of the Huntingtin gene (HTT), leading to the formation of mutant HTT transcripts (muHTT). The toxic gain-of-function of muHTT protein is a major cause of the disease. In addition, it has been suggested that the muHTT transcript contributes to the toxicity. Thus, reduction of both muHTT mRNA and protein levels would ideally be the most useful therapeutic option. We herein present a novel strategy for HD treatment using oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A partial, but significant and potentially long-term, HTT knock-down of both mRNA and protein was successfully achieved. Diminished phosphorylation of HTT gene-associated RNA-polymerase II is demonstrated, suggestive of reduced transcription downstream the ON-targeted repeat. Different backbone chemistries were found to have a strong impact on the ON efficiency. We also successfully use different delivery vehicles as well as naked uptake of the ONs, demonstrating versatility and possibly providing insights for in vivo applications.

Original languageEnglish
JournalNucleic Acids Research
Volume45
Issue number9
Pages (from-to)5153-5169
ISSN0305-1048
DOIs
Publication statusPublished - 2017

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Huntington Disease
Trinucleotide Repeat Expansion
Gene Knockdown Techniques
Messenger RNA
Proteins
Gene Targeting
RNA Polymerase II
Poisons
Life Expectancy
Neurodegenerative Diseases
DNA

Keywords

  • Journal Article

Cite this

Zaghloul, E. M., Gissberg, O., Moreno, P. M. D., Siggens, L., Hällbrink, M., Jørgensen, A. S., ... Smith, C. I. E. (2017). CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression. Nucleic Acids Research, 45(9), 5153-5169. https://doi.org/10.1093/nar/gkx111
Zaghloul, Eman M ; Gissberg, Olof ; Moreno, Pedro M D ; Siggens, Lee ; Hällbrink, Mattias ; Jørgensen, Anna S ; Ekwall, Karl ; Zain, Rula ; Wengel, Jesper ; Lundin, Karin E ; Smith, C I Edvard. / CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression. In: Nucleic Acids Research. 2017 ; Vol. 45, No. 9. pp. 5153-5169.
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Zaghloul, EM, Gissberg, O, Moreno, PMD, Siggens, L, Hällbrink, M, Jørgensen, AS, Ekwall, K, Zain, R, Wengel, J, Lundin, KE & Smith, CIE 2017, 'CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression', Nucleic Acids Research, vol. 45, no. 9, pp. 5153-5169. https://doi.org/10.1093/nar/gkx111

CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression. / Zaghloul, Eman M; Gissberg, Olof; Moreno, Pedro M D; Siggens, Lee; Hällbrink, Mattias; Jørgensen, Anna S; Ekwall, Karl; Zain, Rula; Wengel, Jesper; Lundin, Karin E; Smith, C I Edvard.

In: Nucleic Acids Research, Vol. 45, No. 9, 2017, p. 5153-5169.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

AU - Zaghloul, Eman M

AU - Gissberg, Olof

AU - Moreno, Pedro M D

AU - Siggens, Lee

AU - Hällbrink, Mattias

AU - Jørgensen, Anna S

AU - Ekwall, Karl

AU - Zain, Rula

AU - Wengel, Jesper

AU - Lundin, Karin E

AU - Smith, C I Edvard

N1 - © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

PY - 2017

Y1 - 2017

N2 - Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion of the CAG trinucleotide repeat region in exon 1 of the Huntingtin gene (HTT), leading to the formation of mutant HTT transcripts (muHTT). The toxic gain-of-function of muHTT protein is a major cause of the disease. In addition, it has been suggested that the muHTT transcript contributes to the toxicity. Thus, reduction of both muHTT mRNA and protein levels would ideally be the most useful therapeutic option. We herein present a novel strategy for HD treatment using oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A partial, but significant and potentially long-term, HTT knock-down of both mRNA and protein was successfully achieved. Diminished phosphorylation of HTT gene-associated RNA-polymerase II is demonstrated, suggestive of reduced transcription downstream the ON-targeted repeat. Different backbone chemistries were found to have a strong impact on the ON efficiency. We also successfully use different delivery vehicles as well as naked uptake of the ONs, demonstrating versatility and possibly providing insights for in vivo applications.

AB - Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion of the CAG trinucleotide repeat region in exon 1 of the Huntingtin gene (HTT), leading to the formation of mutant HTT transcripts (muHTT). The toxic gain-of-function of muHTT protein is a major cause of the disease. In addition, it has been suggested that the muHTT transcript contributes to the toxicity. Thus, reduction of both muHTT mRNA and protein levels would ideally be the most useful therapeutic option. We herein present a novel strategy for HD treatment using oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A partial, but significant and potentially long-term, HTT knock-down of both mRNA and protein was successfully achieved. Diminished phosphorylation of HTT gene-associated RNA-polymerase II is demonstrated, suggestive of reduced transcription downstream the ON-targeted repeat. Different backbone chemistries were found to have a strong impact on the ON efficiency. We also successfully use different delivery vehicles as well as naked uptake of the ONs, demonstrating versatility and possibly providing insights for in vivo applications.

KW - Journal Article

U2 - 10.1093/nar/gkx111

DO - 10.1093/nar/gkx111

M3 - Journal article

C2 - 28334749

VL - 45

SP - 5153

EP - 5169

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 9

ER -

Zaghloul EM, Gissberg O, Moreno PMD, Siggens L, Hällbrink M, Jørgensen AS et al. CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression. Nucleic Acids Research. 2017;45(9):5153-5169. https://doi.org/10.1093/nar/gkx111